Lung transplantation is the only effective treatment modality for patients with end-stage lung disease. Ischemia-reperfusion injury, associated with the retrieval, storage and transplantation of the lung is a major immune-independent factor adversely affecting early graft function, graft viability and recipient morbidity and mortality. Marginal donor lungs, are even more susceptible to ischemia-reperfusion injury, and often fail transplantation. Scatter factor/hepatocyte growth factor has significant protective activity in the setting of pulmonary ischemia-reperfusion injury and additionally, favors pulmonary epithelial repair and regeneration. However its clinical use is limited by the logistical difficulties associated with its administration. During our Phase I program, we have identified Refanalin, an organic small molecule scatter factor/hepatocyte growth factor mimetic that improves lung function secondary to ischemia-reperfusion injury, attenuates pulmonary epithelial death and promotes epithelial regeneration. In a preclinical model of lung cold preservation and transplantation, Refanalin treatment reduced roentgenographic alveolar infiltration, improved pulmonary function and preserved pulmonary microarchitecture. The present Phase II makes an in-depth evaluation of Refanalin efficacy in clinically relevant models of lung transplantation. By attenuating allograft dysfunction and preventing allograft failure, Refanalin can reduce recipient morbidity and mortality. By attenuating ischemia- reperfusion injury in the marginal lung, Refanalin can salvage an otherwise discarded organ, and increase the donor pool. PUBLIC HEALTH RELEVANCE: A small molecule cytoprotective that can be added to the lung preservation solution and administered to graft recipient has significant clinical potential in lung and other solid organ transplantation.